Long-term oral administration of dehydroepiandrosterone (DHEA) to various mouse strains inhibits the development of spontaneous breast cancer and chemically induced lung and colon tumors. Topical application of the steroid to mouse skin inhibits DMBA-initiated and TPA-promoted tumors at both the initiation and promotion phase and also inhibits carcinoma and papilloma formation in the complete carcinogenesis system. Although long-term treatment of mice and rats with DHEA produces no apparent side-effects, in some strains of mice and rats DHEA apparently undergoes conversion to an estrogen and is uterotrophic. We have prepared the novel steroid, 3Beta-methylandrost-5-en-17-one (DE-7), which, unlike DHEA, is not uterotrophic in the rat, and according to our early tests, is more active than DHEA in preventing tumorigenesis, DE-7 is a clear potential cancer chemopreventive agent. DHEA is a potent inhibitor of mammalian glucose-6-phosphate dehydrogenase, the first enzyme in the pentose-phosphate shunt, a major source of extra-mitochondrial NADPH. The anti-initiating activity of DHEA very probably results from an inhibition of carcinogen activation, presumably by lowering NADPH levels and reducing the activity of the mixed-function oxidase. DHEA treatment also inhibits O2- formation by TPA stimulated human granulocytes. O2- is generated by an NADPH-dependent oxidase and may play an important role in tumor promotion. In this proposal further studies are planned to help elucidate the mechanism of cancer preventive action of DHEA and DE-7 and to undertake a steroid synthetic and cancer preventive screening program to develop additional non-estrogenic analogs of DHEA that might have greater potency than DE-7.